Lithium anions

Alkyl halide Lithium Anion radical Lithium cation... 

An aza-Darzens reaction, involving the addition of chloromethylphosphonate anions to enantiopure N-sulfinimines, has also been developed by Davis and others for the asymmetric synthesis of aziridine-2-phosphonates [81-84], As an example, treatment of the lithium anion generated from dimethyl chloromethylphos-phonate (93 Scheme 3.30) with N-sulfmimine (Ss)-92 gave the a-chloro-P-amino phosphonate 94, which could be isolated in 51% yield. Cyclization of 94 with n-BuLi gave cis-N-sulfmylaziridine-2-phosphonate 95 in 82% yield [81],... 

The chelated lithium anions 1 and 2, derived from enantiomerically pure tetrahydroisoquino-line-amidines or -oxazolines, exhibit high induced stereoselectivity in alkylation reactions (Section D.l.1.1.1.3.1.). 

Imidate esters can also be generated by reaction of imidoyl chlorides and allylic alcohols. The lithium anions of these imidates, prepared using lithium diethylamide, rearrange at around 0°C. When a chiral amine is used, this reaction can give rise to enantioselective formation of 7, 8-unsaturated amides. Good results were obtained with a chiral binaphthylamine.265 The methoxy substituent is believed to play a role as a Li+ ligand in the reactive enolate. 

Method G is used to introduce the alkyl fragment when less reactive alkenes are employed or for cases where functionality within the dienophilic alkene undergoes reaction with the Grignard reagent. Following this procedure, a lithium anion is first added to the aldehyde 5 at 78 °C.27 After consumption of the aldehyde has been determined by TLC, the dienophile is added and magnesium bromide is introduced. The cycloaddition occurs as the reaction warms to room temperature. In the case of... 

Evans and co-workers demonstrated that rhodium-catalyzed allylic amination of enantiomerically enriched acyclic unsymmetrical allylic carbonates occurs with excellent regio- and enantiospedfidty (Tab. 10.5) [35]. Interestingly, while the classical nitrogen nucleophiles furnished allylic amination products in poor yield and with modest regioselectivity, the lithium anion of N-toluenesulfonyl-N-alkylamines proved optimal, in terms of nucleophilicity and basicity. 

Scheme 10.8 outlines the application of rhodium-catalyzed allyhc amination to the preparation of (il)-homophenylalanine (J )-38, a component of numerous biologically active agents [36]. The enantiospecific rhodium-catalyzed allylic amination of (l )-35 with the lithium anion of N-benzyl-2-nitrobenzenesulfonamide furmshed aUylamine (R)-36 in 87% yield (2° 1° = 55 1 >99% cee) [37]. The N-2-nitrobenzenesulfonamide was employed to facilitate its removal under mild reaction conditions. Hence, oxidative cleavage of the alkene (R)-36 followed by deprotection furnished the amino ester R)-37 [37, 38]. Hydrogenation of the hydrochloride salt of (l )-37 followed by acid-catalyzed hydrolysis of the ester afforded (i )-homophenylalanine (R)-3S in 97% overall yield. 

Tab. 10.6 summarizes the application of this transformation to a variety of racemic secondary allylic carbonates using the lithium anion of 4-methoxy-N-(p-toluidine)-benzene sulfonamide. The excellent regioselectivity obtained for this type of substitution provided an important advance in the synthesis of N-(arylsulfonyl)anihnes using the metal-catalyzed allyhc amination reaction. The allyhc alcohol derivatives examined... 

The combination of allylic amination, ring-closing metathesis, and a free radical cyclization provides a convenient approach to the dihydrobenzo[b]indoline skeleton, as illustrated in Scheme 10.10. The rhodium-catalyzed aUylic amination of 43 with the lithium anion of 2-iodo-(N-4-methoxybenzenesulfonyl)arrihne furnished the corresponding N-(arylsulfonyl)aniline 44. The diene 44 was then subjected to ring-closing metathesis and subsequently treated with tris(trimethylsilyl)silane and triethylborane to afford the dihydrobenzojhjindole derivative 46a in 85% yield [14, 43]. 

That this reaction occurs is shown by electron spin resonance measurements, which indicate the complete disappearance of radicals in the system immediately after the addition of monomer. The dimerization occurs to form the styryl dicarbanion instead of - CH2CH4>CH4>CH2 -, since the former is much more stable. The styryl dianions so-formed are colored red (the same as styryl monocarbanions formed via initiators such as n-butyl-lithium). Anionic propagation occurs at both carbanion ends of the styryl dianion... 

The deprotonation of purines at C-8 to generate the lithium anions is well precedented <1996CHEC-II(7)397> and was used in an attempt to introduce fluorine to C-8 by reaction with iV-fluorobenzenesulfonimide <2005OL3889>. However, the 8-phenylsulfonyl-substituted purine 57 (78% yield) was produced instead of the... 

Reduction of nitro groups. The lithium anion of phthalocyaninecobalt(I), Li[Co(I)Pc], selectively reduces aliphatic and aromatic nitro compounds to primary amines at room temperature in 65 95% yield. Double bonds, nitriles, carhonyl groups, and aryl halides are not reduced. 

A total synthesis of ( )-aromatin has utilized the lithium anion of the dithiane of (E)-2-methyl-2-butenal as a functional equivalent of the thermodynamic enolate of methyl ethyl ketone in an aprotic Michael addition (Scheme 189) (81JOC825). Reaction of the lithium anion (805) with 2-methyl-2-cyclopentenone followed by alkylation of the ketone enolate as its copper salt with allyl bromide delivered (807). Ozonolysis afforded a tricarbonyl which cyclized with alkali to the aldol product (808). Additional steps utilizing conventional chemistry converted (808) into ( )-aromatin (809). 

Chiral a-amino acids The lithium anion of the N-protected glycine amides 3, prepared by reaction of the pyrrolidine with [bis(methylthio)methylene]glycyl pivalic anhydride (DMAP), is alkylated with high diastereoselectivity. The (S)-amino acid (5) is obtained on acid hydrolysis. 

Morton et al.135,141) were the first to study the poly(butadienyl)lithium anionic chain end using (b). They found no evidence of 1,2-chain ends and concluded that only 1,4-structures having the lithium cr-bonded to the terminal carbon were present. A later study by Bywater et al.196), employing 1,1,3,4-tetradeuterobutadiene to minimize the complexity of the spectrum that arises from proton-proton coupling, found that the 1 1 adduct with d-9 fert-butyllithium in benzene exists as a mixture of the cis and trans conformers in the ratio 2.6 1. Glaze et al. 36) obtained a highly resolved spectrum of neopentylallyllithium in toluene and found a cis trans ratio of about 3 1. 

Aluminum ate complexes, (CH3)3SiCH -CHCH2 Al(C2H5)3Li+ (1). The ate complex is prepared by reaction of the lithium anion of allyltrimethylsilane with A1(C2Hs)3. In contrast with the anion of allyltrimethylsilane, which reacts with carbonyl compounds mainly at the y-position, 1 reacts selectively at the a-position (equation T). 

Alkyttdenation. Methylenation of ketones can be effected in 50 99% yield by reaction with the lithium anion (2) of 1 with 0=CR R2 to give a stable adduct (3) that undergoes cycloelimination to alkenes (4) on methylation. When applied to aldehydes, the yield is low except for benzaldehydes or a,/ -unsaturated enals. 

Aldol-type reactions. The lithium anion generated with LDA from 2-ethylpy-ridine chromium tricarbonyl (1) reacts with nonenolizable aldehydes to give a single aldol-type product (2) shown to be the syn-diastereomer. The same reaction, when... 

Chiral primary amines.1 Alkylation of the lithium anion of the N-benzyloxazo-lidinone 1 (derived from valinol) proceeds with high 1,3-stereoselectivity to provide 2 in 75-96% de, which can be improved by crystallization or chromatography. The products can be degraded to (R)-primary amines (5) by hydrolysis (3) and oxidation to an imine (4), which is then hydrolyzed to an amine. Slight racemization is observed in these last steps. 

Z)-l-Trimethylsilyl-l-alkenes.1 The a-trimethylsilyl diazoalkanes (2), prepared by reaction of primary halides (1) with the lithium anion of trimethylsilyl diazomethane, decompose on treatment with rhodium(II) pivalate [superior in this case to rhodium(II) acetate] to (Z)-l-trimethylsilyl-1-alkenes. 

Tetrahydrofuran (3.2 ml) and S-(+)-3-chloro-l,2-propanediol (0.299 ml, 3.58 mmol, 1.19 eq) are mixed. The mixture of THF (3.2 ml) and S-(+)-3-chloro-1,2-propanediol (0.299 ml, 3.58 mmol, 1.19 eq) is cooled to -16°C and potassium t-butoxide (3.2 ml, 1.0 M) in THF (3.2 mmol, 1.07 eq) is added at less than -10°C. The resulting slurry is stirred at -14-0°C for 1 hour. Then added to the lithium anion mixture while maintaining both mixtures at 0°C, then rinsed in with THF (2 ml). The resultant slurry is stirred at 20-23°C for 2 hour and then cooled to 6°C and a mixture of citric acid monohydrate (0.4459 g, 2.122 mmol, 0.705 eq) in water (10 ml) is added. The resultant liquid phases are separated and the lower aqueous phase is washed with ethyl acetate (12 ml). The organic layers are combined and solvent is removed under reduced pressure until a net weight of 9.73 g remains. Heptane (10 ml) and water (5 ml) are added and solvent is removed 4-nitrobenzenesulfonyl chloride y reduced pressure until a total volume of 5 ml remains. The precipitated product is collected by vacuum filtration and washed with water (7 ml). The solids are dried in a stream of nitrogen to give (R)-[N-3-(3-fluoro-4-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol. 

The lithium anion of chloromethyl phenyl sulfoxide reacts with tetrahydrofuran-2-ones 1011 to afford a diastereo-meric mixture of hemiacetal adducts 1012, the potassium enolate of which is treated with /-BuLi followed by addition of a proton source leading to to-hydroxyalkyl ketenes 1013, which themselves cyclize to 6-substituted tetrahydropyran-2-ones in excellent overall yield (Scheme 263) <1998TL9215>. 

As outlined in Scheme 28, the synthesis of the P-ketophosphonate 131 began with a one-pot anh -aldol/reduction step between ethyl ketone 101 and aldehyde 133, giving the 1,3-syn diol 134 (>30 ldr) [130, 132-136, 145, 146], The diol 134 was then converted into the carboxylic acid 135 in six steps. Completion of the subunit 131 required conversion into the acid chloride and reaction with the lithium anion of methyl-(di-l,l,l-trifluoroethyl)-phosphonate. The C9-C24 aldehyde 132 was prepared in two steps from 136, an intermediate from previous routes [55-58], The Still-Gennari-type coupling of 131 and 132 was readily achieved via treatment with... 

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